DEVELOPMENT OF IGFBP-3 THERAPY IN MEN WITH PROSTATE CANCER In preliminary data derived with this SPORE grant, we demonstrated interactions of IGFBP-3 with mitochondria! and nuclear apoptosis-related proteins and showed that IGFBP-3's action requires rapid internalization, phosphorylation, and association with the multi-compartmental nuclear receptors RXRa and Nur77 leading to both rapid induction of apoptosis pathways. Particularly, we described that the nucleo- mitochondrial translocation of Nur77 in response to IGFBP-3 treatment is a key event in the IGFBP-3 cascade and could serve as a biomarkerfor IGFBP-3 responsiveness. Importantly, we have also shown that the in vivo administration of IGFBP-3 to xenograft bearing mice results in substantial tumor suppression and inhibition of angiogenesis and that the effects of IGFBP-3 in vivo are observed when given as a single therapy, and are enhanced in combination with other agents. Our work has been instrumental in advancing this field to its current state, and in this SPORE renewal we propose to further investigate the role of IGFBP- 3 as a therapy for men with prostate cancer. Our specific aims are to (1) Develop histopathology assays for IGFBP-3 pathway molecules in prostate cancer and evaluate of their role in determining disease prognosis and their ability to serve as surrogate tissue biomarkers of IGFBP-3 activity on prostate cancer in vivo, (e. g. Nur77 subcellular localization);and to determine, using the SPORE tissue array resource, if baseline intra tumor staining levels of IGFBP-3, Nur77, and RXRa predict the clinical outcome of patients with prostate cancer. (2) Conduct a a Phase 1 b dose response neoadjuvant trial of IGFBP-3 in men with CaP. The primary goals of the study are to assess toxicity and to identify an active dose as defined by molecular induction of apoptosis using assays that include those developed in Aim 1. Secondary goals will be to use genomic and proteomic analyses to identify additional surrogate markers of treatment. (3) Optimize IGFBP-3 treatment of prostate cancer in in vivo mouse models, prior to initiating a larger phase 2 study. This Aim is a reverse translation that will build upon the preceding clinical study. Our goals are to identify drugs that synergize with IGFBP-3, such as IGF receptor inhibitors, EGF receptor antagonists and nutritional agents including Pom X. Together, these efforts will serve to promote the development of rational IGFBP-3-related therapies and tools to assess its efficacy in prostate cancer. As the first clinical trials targeting other components of the IGF axis are already underway, we believe that IGFBP-3 will have additional tumor suppressive effects given its IGF-dependent and -independent apoptosis-promoting properties. If successful, our findings may provide new avenues for the treatment of this disease and pave the way towards larger clinical studies involving IGFBP-3.